Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed promising antitumor activity in both pre-clinical and clinical studies. Here, we reported the results of F plus S from a gastric cancer (GC) cohort in an open-label, multicenter, single-arm phase II study in China. Advanced gastric or GEJ adenocarcinoma pts with PD-L1 status of CPS ≥1, who had no prior systemic therapy or had failed at least first-line treatment were enrolled. Eligible pts received F (5 mg, 2 weeks on/1 week off, orally, once daily) plus S (200 mg, IV, every 3 weeks) in 21-day cycles, until disease progression or unacceptable toxicity. Treatment of S was allowed for up to 24 months (mo). The primary endpoint was ORR per RECIST v1.1. As of February 28, 2023, 27 pts were enrolled and received F plus S, including 20 treatment-naive pts (i.e.: 1st -line pts), and 7 pts with prior treatment (i.e.: ≥ 2nd-line pts). Median (range) age was 63.71 (35.8, 74.6) years. There were 8 (29.6%), 9 (33.3%), and 8 (29.6%) pts with PD-L1 status of 1≤ CPS <5, 5≤ CPS<10, and 10≤ CPS, which was tested by the central lab, respectively. Median duration of treatment of F and S were 6.90 and 7.13 months. Among tumor evaluable pts (N=18 for 1st -line pts, N=6 for ≥ 2nd-line pts), confirmed ORRs were 72.2% and 33.3% in 1st -line pts and ≥ 2nd-line pts, respectively; clinical responses correlated with level of PD-L1 status. DCRs were 100% and 83.3% in 1st -line pts and ≥ 2nd-line pts; median TTR reached 2.7 mo and 2 mo in 1st -line pts and ≥ 2nd-line pts. 9-month PFS rates were 63.8% and 50.0% in 1st -line pts and ≥ 2nd-line pts. Median PFS and OS were not mature. Common (≥20%) treatment-related treatment-emergent adverse events included proteinuria (48.1%), hypothyroidism (40.7%), aspartate aminotransferase increased (25.9%), alanine aminotransferase increased (22.2%), hypertension (22.2%), and weight decreased (22.2%). F plus S provided favourable efficacy and manageable toxicity profile in pts with advanced gastric or GEJ adenocarcinoma, especially for pts who cannot tolerate chemotherapy.

Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed promising antitumor activity in both pre-clinical and clinical studies. Here, we reported the results of advanced NSCLC cohort with PD-L1-positive expression in an open-label, multi-cohort, single-arm phase 2 study to evaluate the safety and efficacy of F+S. Eligible advanced NSCLC pts were those who failed, could not tolerate, were not suitable or unwilling to receive standard treatment; were PD-L1 positive (defined as PD-L1 TPS expression ≥1%); and were without EGFR, ALK or ROS1 genetic alteration if non-sq-NSCLC. Enrolled pts received 21-day cycles of F (5 mg, orally QD, 2 weeks on/1 week off) plus S (200 mg IV, Q3W) until disease progression or intolerable toxicity or the maximum duration of treatment with S (24 mo). The primary endpoint was ORR per RECIST 1.1. As of May 31, 2023, 13 treatment-naïve pts were enrolled and received treatment of F+S. Median age, 69 yrs (range: 36-75); male, 12 (92.3%) pts; sq-NSCLC, 7 (53.8%) pts; adenocarcinoma, 6 (46.2%) pts. Pts with PD-L1 TPS ≥50% and <50% were 6 (46.2%) and 7 (53.8%), respectively. The median follow-up duration was 17.7 (95%CI: 10.4, 18.4) mo. Among 12 pts with at least one post-baseline tumor assessment, the confirmed ORR was 50.0% (95%CI: 21.1%, 78.9%); DCR was 100% (95%CI: 73.5%, 100%); the median DoR, PFS, and OS were all not reached. 15mo-PFS rate was 55.9% (95%CI: 24.0%, 79.0%), and 18mo-OS rate was 60.6% (95%CI: 29.4%, 81.4%). When stratified by PD-L1 level (TPS ≥50% vs <50%), 15mo-PFS rate were 66.7% (95%CI: 19.5%, 90.4%) vs 42.9% (95%CI: 5.8%, 77.7%), 18mo-OS rate were 66.7% (95%CI: 19.5%, 90.4%) vs 53.6% (95%CI: 13.2%, 82.5%). The median treatment duration of F and S were both 8.3 mo (range 0.7-18.6). All pts experienced TEAEs, and the most common (≥10%) ≥G3 treatment related TEAE was only blood pressure increased (15.4%). F plus S showed a promising antitumor activity and manageable toxicity for advanced NSCLC with PD-L1-positive status. This study might represent a potential treatment option for these pts, especially for pts who can not tolerate chemotherapy.

Fruquintinib (F, a highly selective VEGFR inhibitor) plus sintilimab (S, an anti-PD-1 monoclonal antibody) showed promising antitumor activity in both pre-clinical and clinical studies. Here, we reported the results of F plus S from CC cohort in an open-label, multicenter, single-arm phase 2 study. Pts with pathologically confirmed advanced CC who had failed at least first-line platinum-containing treatment, or experienced intolerable toxicity during treatment, or were unable to receive standard therapy were eligible. Eligible pts received F (5 mg, 2 weeks [wk] on/1 wk off, orally, once daily) plus S (200 mg, IV, every 3 wk) in 21-day cycles, until disease progression or unacceptable toxicity. Treatment of S was allowed for up to 24 months (mo). The primary endpoint was ORR per RECIST v1.1. As of May 30, 2023, 34 pts were successfully enrolled and received F plus S, median follow-up duration was 16.4 mo. Median (range) age was 56 (26.2, 73.7) yrs. 6 pts (17.6%) were treatment naïve (naïve pts); 28 pts (82.4%) had received at least first-line treatment (treated pts), including bevacizumab (5/28), for advanced disease. 25 pts (73.5%) had received pelvic radiation therapy. There were 24 pts (70.6%) with PD-L1 status of CPS ≥1. Among tumor evaluable naïve and treated pts, confirmed ORR (cORR) were 50.0% (PR 3/6) and 29.6% (CR 1/27 and PR 7/27); median TTR were 2.7 and 3.1 mo; DCR were both 100%. In naïve (N=6) and treated (N=28) pts, mPFS were 10.3 and 8.2 mo, 15mo-OS rate were 83.3% and 70.0%. In tumor evaluable treated pts stratified by CPS ≥1 vs <1 (N= 17 vs 8), cORR was 41.2% vs 12.5%; in treated pts (N=18 vs 8), mPFS was 19.4 vs 5.2 mo; mOS was not reached vs 13.9 mo, 15mo-OS rate was 76.0% vs 50.0%. All pts experienced TEAEs, and the most common TEAEs included proteinuria (64.7%), hypothyroidism (61.8%), asthenia (44.1%), hyperthyroidism (44.1%), palmar-plantar erythrodysaesthesia syndrome (44.1%), anaemia (41.2%) and urinary tract infection (41.2%). F plus S provided favorable efficacy in advanced CC pts, especially for treated PD-L1 CPS ≥1 pts. This combination treatment also showed manageable toxicity profile consistent with that seen in other cohorts.

Purpose: This study aims to identify the role of PD-1/PD-L1 pathway activation in determining clinical characteristics and treatment outcomes in pulmonary tuberculosis. Methods: We prospectively enrolled PTB, LTBI, and non-TB, non-LTBI subjects. Expression of PD-1 and PD-L1 on T cells and on PBMCs was measured. Immunohistochemistry and immunofluorescence were used to visualize PD-1- and PD-L1-expressing cells in lung tissues. The findings in humans were verified in THP-1 monocyte cell lines and mouse macrophages with Mycobacterium tuberculosis (MTB) related stimulation. Results: A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with positive smear and sputum smear/culture unconversion at 1 and 2 months displayed higher PD-L1 expression on monocytes before treatment initiation. IHC analysis demonstrated abundant PD-L1-expressing macrophages in lung tissues from PTB patients. In vitro MTB whole cell lysate/EsxA stimulation of THP-1 cells and mouse macrophages demonstrated increased PD-L1 expression, which can be down-regulated by co-treatment of NF-kB pathway inhibitor. IF analysis demonstrated co-localization of PD-L1 and macrophages were identified in lung tissues from mice with intratracheal injection of heat-killed MTB. Conclusions: Increased expression of PD-L1 on monocytes in PTB patients correlated with bacterial burden and treatment outcomes. Cell and mice models confirm that MTB-related stimulation increased PD-L1 expression in macrophages.

Background: No validated biomarkers currently exist for predicting the efficacy outcomes in patients with neuroendocrine tumors (NETs) treated with antiangiogenic therapy. We aimed to evaluate the association between treatment-related adverse events (TRAEs) and efficacy outcomes of surufatinib in patients with advanced NET. Patients and methods: We included patients with NET treated with surufatinib in two multicenter, randomized, double-blind, placebo-controlled, phase III trials (SANET-p and SANET-ep) in this study. The main exposure was the presence of any of the TRAEs including hypertension, proteinuria, and hemorrhage in the first 4 weeks of surufatinib treatment. The primary outcome of the study was investigator-assessed progression-free survival (PFS). PFS outcomes were estimated using the Kaplan-Meier method with the log-rank test. Hazard ratios (HRs) were calculated by using univariable and multivariable Cox proportional hazard regression models. Blinded independent image review committee (BIIRC) assessments and 4-week landmark analysis were also performed as supportive evaluations. Results: During the study period, a total of 242 patients treated with surufatinib were included in the analysis, and 164 (68%) patients had at least one of hypertension, proteinuria, and hemorrhage in the first 4 weeks of treatment. The presence of TRAEs in the first 4 weeks was associated with prolonged median PFS [11.1 versus 9.2 months; HR 0.67, 95% confidence interval (CI) 0.47-0.97; P = 0.036]. In multivariable Cox regression analysis, the presence of TRAEs was also significantly associated with longer PFS (HR 0.65, 95% CI 0.44-0.97; P = 0.035). Similar results were obtained in the BIIRC assessments and 4-week landmark analysis. Conclusions: Treatment-related hypertension, proteinuria, and hemorrhage could be potential biomarkers to predict antitumor efficacy of surufatinib in patients with advanced NET. Future prospective studies are needed to validate the findings.

Surufatinib shows good efficacy in treating advanced NET. To better assist therapeutic decision-making and improve outcomes, candidates who may benefit from surufatinib need to be identified in advance. This study aimed to seek novel imaging biomarkers for stratifying treatment response by developing a radiomics-based machine learning model. Imaging features were extracted from liver lesions in portal phase of pretreatment abdominal contrast-enhanced CT. Two experienced radiologists independently delineated the lesions. Baseline clinical variables and the overall response (RECIST 1.1) were added into model training. Patients were divided into responder and stable disease (SD) groups. Responder was defined as target lesion size reduced by over 15%, and SD as target lesion size changed within -15%∼20%. Data were randomly assigned in 8:2 as training set and validation set. Features were selected by ElasticNet. The model was comprised of two-layer classifiers. The first-layer classifier (FLC) was composed of random forest, support vector machine, and Bayes algorithms, followed by logistic regression as the second-layer classifier (SLC). The FLC was validated using 5-fold cross-validation. The output from FLC, the predicted probabilities of each cross-validation set, was then used as input to train SLC for predicting responder. The performance of the model was evaluated in validation set with area under the curve (AUC), specificity, sensitivity, and accuracy. A total of 217 patients in 3 trials (NCT02267967, NCT02588170, NCT02589821) were included (responder vs SD: 95 vs 122). Among 55 radiomics features and 6 clinical factors, ten variables were selected, including coarseness, compactness, skewness, kurtosis, busyness, long-run matrix homogeneousness, cumulative intensity, feature homogeneity and mean HU value of lesion, diagnosis-to-medication time. The model performance achieved an accuracy of 68%, with an AUC of 0.67, sensitivity of 63%, and specificity of 71%. This preliminary result demonstrated the radiomics-based machine learning model could predict treatment responses in patients with advanced NET.

Patritumab deruxtecan is an investigational human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload, and it has shown preliminary antitumor activity in patients with previously treated metastatic or locally advanced epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) in an ongoing phase 1 study (NCT03260491). Here we present initial observations from comprehensive genomic profiling in tumor tissue and circulating tumor DNA (ctDNA), tumor HER3 expression and its association with prior treatment and with the clinical activity of patritumab deruxtecan, and dynamic changes in a ctDNA panel during study treatment.

The epidermal growth factor receptor-tyrosine kinase inhibitots (EGFR-TKIs) have become the mainstay treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). Although it provides significant improvement in objective response rate and progression-free survival, disease progression in inevitable and subsequent therapy remains challenge. Recently, there are growing studies focused on the combination treatment strategy to improve the treatment outcome. In current study, we will evaluate the role of residual tumor resection during the use of EGFR-TKI in patients with advanced EGFR-mutant NSCLC.

BackgroundPatients (pts) with advanced SCLC have a rapid relapse after 1L treatment, and only one approved agent (topotecan) for 2L treatment. Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in a neuroendocrine carcinoma cohort in a trial evaluating S + T in pts with selected solid tumors. Here, we report the safety and efficacy results in the SCLC cohort.MethodsIn this cohort of the multicenter, multi-cohort, single-arm phase 2 study (NCT04169672), adults (18-75) with advanced SCLC who had failed 1L systemic chemotherapy (platinum-based systemic chemotherapy) were eligible, and received 3-week cycles of S (250 mg orally, QD) plus T (240 mg IV, Q3W). The primary endpoint was objective response rate (ORR) per RECIST 1.1.ResultsAt cutoff date (Aug 1, 2021), 20 pts (median age, 58 yrs; ECOG=1, 17 pts; PD-L1 CPS<1, 16 pts) were enrolled and received combination treatment. Median treatment duration of S and T was both 3 mo. Among pts with at least one post-baseline tumor assessment (evaluable pts, n=19), the confirmed ORR (2 PRs) was 10.5% (95%CI 1.3-33.14), DCR was 94.7% (95%CI 73.97-99.87). Median DoR was not reached. Median PFS (mPFS) was 2.96 mo (95%CI 2.79-4.11), and median OS (mOS) was 10.94 mo (95%CI 4.96-NR). In platinum-sensitive (n=8) and -resistant (n=12) subgroups (defined as pts with disease relapsed ≥90 days and <90 days, respectively, after platinum-based chemotherapy), the confirmed ORR (95%CI) in evaluable pts (n=8 and 11) were 0 and 18.2% (2.28-51.78), DCR (95%CI) were 87.5% (47.35-99.68) and 100% (71.51-100), respectively; mPFS (95%CI) were 3.4 mo (1.38-5.59) and 2.96 mo (2.69-4.11), and mOS (95%CI) were not reached (median duration of follow up, 11.10 mo) and 8.87 mo (4.34-NR), respectively. Nine (45%) pts reported TRAEs of grade ≥3, most commonly (≥2 pts) with hypertriglyceridemia and hypertension, both with 2 pts. No TRAEs led to treatment discontinuation or death.ConclusionsS + T showed a promising anti-tumor activity and an acceptable toxicity for 2L treatment of SCLC. The combination of the two agents might be a novel 2L therapeutic option for SCLC.Clinical trial identificationNCT04169672.Editorial acknowledgementWe acknowledge Xia Yin (medical writer of HUTCHMED) for the abstract editing work.Legal entity responsible for the studyHUTCHMED.FundingHUTCHMED.DisclosureJ. Zhou, H. Shi, P. Tan, S. Fan, W. SuFinancial Interests, Personal, Full or part-time Employment: HUTCHMED. All other authors have declared no conflicts of interest. BackgroundPatients (pts) with advanced SCLC have a rapid relapse after 1L treatment, and only one approved agent (topotecan) for 2L treatment. Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in a neuroendocrine carcinoma cohort in a trial evaluating S + T in pts with selected solid tumors. Here, we report the safety and efficacy results in the SCLC cohort. Patients (pts) with advanced SCLC have a rapid relapse after 1L treatment, and only one approved agent (topotecan) for 2L treatment. Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in a neuroendocrine carcinoma cohort in a trial evaluating S + T in pts with selected solid tumors. Here, we report the safety and efficacy results in the SCLC cohort. MethodsIn this cohort of the multicenter, multi-cohort, single-arm phase 2 study (NCT04169672), adults (18-75) with advanced SCLC who had failed 1L systemic chemotherapy (platinum-based systemic chemotherapy) were eligible, and received 3-week cycles of S (250 mg orally, QD) plus T (240 mg IV, Q3W). The primary endpoint was objective response rate (ORR) per RECIST 1.1. In this cohort of the multicenter, multi-cohort, single-arm phase 2 study (NCT04169672), adults (18-75) with advanced SCLC who had failed 1L systemic chemotherapy (platinum-based systemic chemotherapy) were eligible, and received 3-week cycles of S (250 mg orally, QD) plus T (240 mg IV, Q3W). The primary endpoint was objective response rate (ORR) per RECIST 1.1. ResultsAt cutoff date (Aug 1, 2021), 20 pts (median age, 58 yrs; ECOG=1, 17 pts; PD-L1 CPS<1, 16 pts) were enrolled and received combination treatment. Median treatment duration of S and T was both 3 mo. Among pts with at least one post-baseline tumor assessment (evaluable pts, n=19), the confirmed ORR (2 PRs) was 10.5% (95%CI 1.3-33.14), DCR was 94.7% (95%CI 73.97-99.87). Median DoR was not reached. Median PFS (mPFS) was 2.96 mo (95%CI 2.79-4.11), and median OS (mOS) was 10.94 mo (95%CI 4.96-NR). In platinum-sensitive (n=8) and -resistant (n=12) subgroups (defined as pts with disease relapsed ≥90 days and <90 days, respectively, after platinum-based chemotherapy), the confirmed ORR (95%CI) in evaluable pts (n=8 and 11) were 0 and 18.2% (2.28-51.78), DCR (95%CI) were 87.5% (47.35-99.68) and 100% (71.51-100), respectively; mPFS (95%CI) were 3.4 mo (1.38-5.59) and 2.96 mo (2.69-4.11), and mOS (95%CI) were not reached (median duration of follow up, 11.10 mo) and 8.87 mo (4.34-NR), respectively. Nine (45%) pts reported TRAEs of grade ≥3, most commonly (≥2 pts) with hypertriglyceridemia and hypertension, both with 2 pts. No TRAEs led to treatment discontinuation or death. At cutoff date (Aug 1, 2021), 20 pts (median age, 58 yrs; ECOG=1, 17 pts; PD-L1 CPS<1, 16 pts) were enrolled and received combination treatment. Median treatment duration of S and T was both 3 mo. Among pts with at least one post-baseline tumor assessment (evaluable pts, n=19), the confirmed ORR (2 PRs) was 10.5% (95%CI 1.3-33.14), DCR was 94.7% (95%CI 73.97-99.87). Median DoR was not reached. Median PFS (mPFS) was 2.96 mo (95%CI 2.79-4.11), and median OS (mOS) was 10.94 mo (95%CI 4.96-NR). In platinum-sensitive (n=8) and -resistant (n=12) subgroups (defined as pts with disease relapsed ≥90 days and <90 days, respectively, after platinum-based chemotherapy), the confirmed ORR (95%CI) in evaluable pts (n=8 and 11) were 0 and 18.2% (2.28-51.78), DCR (95%CI) were 87.5% (47.35-99.68) and 100% (71.51-100), respectively; mPFS (95%CI) were 3.4 mo (1.38-5.59) and 2.96 mo (2.69-4.11), and mOS (95%CI) were not reached (median duration of follow up, 11.10 mo) and 8.87 mo (4.34-NR), respectively. Nine (45%) pts reported TRAEs of grade ≥3, most commonly (≥2 pts) with hypertriglyceridemia and hypertension, both with 2 pts. No TRAEs led to treatment discontinuation or death. ConclusionsS + T showed a promising anti-tumor activity and an acceptable toxicity for 2L treatment of SCLC. The combination of the two agents might be a novel 2L therapeutic option for SCLC. S + T showed a promising anti-tumor activity and an acceptable toxicity for 2L treatment of SCLC. The combination of the two agents might be a novel 2L therapeutic option for SCLC.